PROJECT SUMMARY In 2013, the Centers for Disease Control and Prevention (CDC) assigned its highest antibiotic resistance threat level to carbapenem-resistant Enterobacteriaceae (CRE). CRE are resistant to nearly all routinely used antibiotics with gram-negative coverage and have been implicated in several high-profile nosocomial outbreaks in United States (U.S.) facilities. Although in past outbreaks institutions have deployed aggressive and highly bundled responses, this ?kitchen sink? approach is unlikely to be resource- or cost-effective as CRE become endemic in the U.S. Evidence-based CRE policies are necessary, but fundamental gaps in knowledge remain. In particular, heterogeneous mechanisms encode carbapenem resistance in CRE, which are broadly classifiable by whether carbapenem resistance does (?CP-CRE?) or does not (?non-CP-CRE?) arise from carbapenemase production. Until recently resistance testing was limited in clinical settings, but this landscape is changing with the rollout of commercially available assays for identifying carbapenemase production. However, data on the prevalence of CP-CRE and non-CP-CRE in U.S. patients, especially among high-risk hospitalized populations, are limited. Moreover, some evidence suggests that propensity for intra-facility spread differs between CP-CRE and non-CP-CRE, but rigorous data are lacking. Evaluating epidemiological differences in CRE resistance types is essential to establishing public health priorities for CRE prevention in U.S. healthcare facilities. Aim 1 will evaluate the prevalence of and pre-admission risk factors for rectal colonization with CP-CRE and non-CP-CRE in a cohort of approximately 1900 patients admitted to the medical intensive care unit (MICU) and comprehensive transplant unit (CTU) at The Johns Hopkins Hospital. Risk factors will be analyzed with machine learning methodologies in order to develop a user-friendly decision tree to identify patients at high-risk of CP-CRE and/or non-CP-CRE carriage for future targeted surveillance screening. Aim 2 will utilize serially collected rectal swabs, in conjunction with clinical and environmental data, to estimate the incidence of nosocomial CP-CRE and non-CP-CRE colonization and to evaluate the contribution of asymptomatic CRE carriers and individual-level risk factors on a patient's risk of CRE acquisition during unit hospitalization. Strain-typing and other analyses as needed (e.g., whole genome sequencing) will be available to ascertain transmission events. This will be the first study in a U.S. hospital to investigate CRE spread associated exclusively with asymptomatic carriers and stratified by resistance type in a non-outbreak setting. The broad, long-term goals of this proposal are to advance our understanding of the epidemiology of CRE colonization and the implications of CRE resistance mechanisms to routes of nosocomial acquisition in order to guide CRE control policies and resource prioritization in U.S. healthcare facilities.